Binding affinities of retinoids to fetal cellular retinoic acid-binding protein (CRABP) in relation to their teratogenic potency in hamsters

Howard, W. Brian; Sharma, Raghubir P.; Willhite, Calvin C.; Dawson, Marcia I.

doi:10.1016/0006-2952(90)90568-6

Cited by 21 publications

(5 citation statements)

References 23 publications

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“…Although many biologically active retinoids bind to CRABP [54,55], a number have been identified that do not bind [56,57]. An examination of the teratogenic potency in hamsters of 14 retinoid analogues showed that active retinoids bind CRABP, but inactive ones do not [58]. Some of the CRABP-binding and biologically active retinoids are conformationally constrained by fusion of the p-ionone ring to the isoprene tail.…”

Section: Binding Of Retinoid Derivativesmentioning

confidence: 99%

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Crystal structures of cellular retinoic acid binding proteins I and II in complex with all-trans-retinoic acid and a synthetic retinoid

et al. 1994

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The retinoid-binding site in CRABPs differs significantly from that observed in CRBP. Structural changes in three juxtaposed areas of the protein create a new, displaced binding site for RA. The carboxylate of the ligand interacts with the expected trio of residues (Arg132, Tyr134 and Arg111; CRABP II numbering). The RA ligand is almost flat with the beta-ionone ring showing a significant deviation (-33 degrees) from a cis conformation relative to the isoprene tail. The edge atoms of the beta-ionone ring are accessible to solvent in a suitable orientation for presentation to metabolizing enzymes. The bulkier synthetic retinoid causes small conformational changes in the protein structure.

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Section: Binding Of Retinoid Derivativesmentioning

confidence: 99%

“…TTNPB (Fig. 1) is a biologically very active retinoid built up from a fused ring system and a modified tail that shows high affinity for CRABP [58]. This molecule is easily overlayed on the RA and compound 19 structures (Figs 9c and 9d).…”

Section: Cellular Retinoic Acid Binding Protein Complexes Kleywegt Etmentioning

confidence: 99%

Crystal structures of cellular retinoic acid binding proteins I and II in complex with all-trans-retinoic acid and a synthetic retinoid

et al. 1994

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“…g Bernard, 1993;Czernielewski, Michel, Bouclier, Baker, & Hensby, 2001. Howard, Sharma, Willhite, & Dawson, 1990;Allenby et al, 1993;Bernard, 1993. b Allenby et al, 1993;Nau, 1994. c Howard, Sharma, Willhite, & Dawson, 1990;Nau, 1994. d Acitretin is the active metabolite of etretinate; thus, the potential for interaction with CRABP is considered to be the same for both compounds; Pilkington & Brogden, 1992. e Bernard, 1993. off-target toxicities, all three of the third-generation retinoids can be administered through topical application in order to minimize systemic exposures. In fact, both adapalene and tazarotene have been specifically formulated for topical use only.…”

Section: Vitamin a And The Pharmaceutical Retinoidsmentioning

confidence: 99%

“…For example, of the first-generation retinoids, tretinoin has been shown to have the greatest relative binding affinity for the RAR receptors, and only alitretinoin binds to the RXR receptors. Furthermore, isotretinoin has been variably reported to not bind with CRABPs or to bind with only very low affinity (Howard, Sharma, Willhite, & Dawson, 1990;Nau, 1994); this fact-in combination with differences in placental transfer and the drug's rapid clearance in rodents-explains the relatively high teratogenic LOAEL for isotretinoin reported in the rat (Nau, 1994). In contrast, it should be noted that a much lower teratogenic dose for isotretinoin has been reported in humans (Teratology Society, 1987).…”

Section: Relative Teratogenicitymentioning

confidence: 99%

Teratogen update: Topical use and third‐generation retinoids

Williams

Pace

DeSesso

2020

Birth Defects Research

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The first pharmaceutical retinoids approved by the U.S. Food and Drug Administration were given black‐box warnings against their use in pregnancy due to potential teratogenic effects. These first‐ and second‐generation retinoids were initially formulated for oral dosing and are structurally very similar to vitamin A, which has beneficial effects on skin as well as plays a vital role in driving healthy embryogenesis. Some of these early retinoids have since been reformulated for topical application, which has resulted in their diminished potential for systemic exposures. Additionally, rational drug design has been applied to create today's third‐generation retinoids (adapalene, tazarotene, and bexarotene). These compounds include aromatic rings within their molecular cores to provide structural rigidity that contrasts with the flexible aliphatic backbone of vitamin A and the earlier generations of retinoids, and thus limits their off‐target activity. As a result of these design features, the teratogenic potential in animals of the third‐generation retinoids and those reformulated for topical use is generally less than seen with oral administration of earlier generations of retinoids. The available, but limited, epidemiologic data further show little‐to‐no teratogenic potential associated with real‐life use of these compounds in humans. Given the paucity of epidemiologic data available at this time, however, it is recommended that the use of topical retinoids during pregnancy be avoided. However, in circumstances when inadvertent exposure in pregnancy may occur, the available data provide some reassurance that adverse pregnancy outcomes are unlikely.

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“…To determine nonspecific binding, 100 nM RA was added to the controls. The percent displacement of [3H]RA by retinoids was calculated as described previously (24).…”

Section: Binding Affinity Of Retinoids By Displacement Assaymentioning

confidence: 99%

Characterization of heterologously expressed recombinant retinoic acid receptors with natural or synthetic retinoids

Kim

Sharma

1994

J. Biochem. Toxicol.

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The first step in retinoid action is binding to their nuclear receptors. Therefore, characterization of binding characteristics of retinoids is of major importance. Human retinoic acid receptors alpha (hRAR alpha), hRAR beta, and mouse RAR gamma (mRAR gamma) were expressed heterologously in Escherichia coli as a recombinant glutathione S-transferase (GST) fusion protein. The expressed fusion proteins were functional and bound specifically to the all-trans-retinoic acid (RA). The dissociation constants (Kd) for RA were 1.4 nM for GST-hRAR alpha, 1.4 nM for GST-hRAR beta, and 3.3 nM for GST-mRAR gamma, respectively. The fusion proteins were further used for competitive displacement assays to determine the displacement constant (DC50) for other selected retinoids. All-trans-RA and 4-oxo-all-trans-RA have high affinity with all three receptors (DC50 = 0.8-55 nM). The 13-cis RA binds to hRAR alpha with low affinity, but not to other RARs evaluated here. All-trans-N-ethylretinamide, all-trans-retinylacetate, and an ethyl ester of tetrahydronaphthalene derivative had no affinity to any RARs. The hRAR alpha and mRAR gamma receptors did not bind a naphthalene carboxylic acid derivative of RA, but hRAR beta binds this chemical with high affinity. Results indicated that the three recombinant proteins were functional in binding various RA congeners. The affinity and binding data of these retinoids were compared to their observed teratogenic activity.

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Binding affinities of retinoids to fetal cellular retinoic acid-binding protein (CRABP) in relation to their teratogenic potency in hamsters

Cited by 21 publications

References 23 publications

Crystal structures of cellular retinoic acid binding proteins I and II in complex with all-trans-retinoic acid and a synthetic retinoid

Crystal structures of cellular retinoic acid binding proteins I and II in complex with all-trans-retinoic acid and a synthetic retinoid

Teratogen update: Topical use and third‐generation retinoids

Characterization of heterologously expressed recombinant retinoic acid receptors with natural or synthetic retinoids

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